Few clinical niches are currently spared from the reach of novel genomic technologies. Molecular analysis technologies enable the parsing of biological pathways with previously unattainable granularity. Stratifying patient populations based on their genetic markers is becoming a clinical reality. In the near future, some of these markers may become targets for developing better treatment options.
Utilization of molecular diagnostics in specific clinical scenarios, however, still needs to be significantly optimized. In particular, results from these novel assays need to be interpreted in a context of traditional clinicopathologic criteria, particularly in situations where the novel and the traditional measurements produce conflicting results. But even with validation of novel technologies for molecular diagnostics still ongoing, clinicians are already able to apply the first insights to patient treatment.
CHI’s upcoming “Molecular Medicine” conference will explore new frontiers of DNA-based diagnostic technologies. Several cutting-edge technologies may be discussed that have a potential to make a profound difference in our way of diagnosing and treating disease.
The potential for prenatal diagnosis would explode if clinicians could avoid amniocentesis and easily access fetal DNA from maternal blood. Most current maternal screening tests are based on associations between various maternal blood levels and fetal outcomes and can only indirectly assign a risk of a particular fetal abnormality. By contrast, amniocentesis enables direct sampling of fetal DNA for diagnostic purposes.
A small amount of amniotic fluid, which contains fetal cells, is extracted from the amniotic sac surrounding a developing fetus, and the fetal DNA or chromosomes can then be evaluated for genetic abnormalities. But amniocentesis is expensive and can lead to complications including miscarriage. The work of Y. M. Dennis Lo, M.D., a professor at the Chinese University of Hong Kong, has resulted in the ability to detect cell-free fetal DNA in the maternal circulation (ccff DNA).
In the maternal circulation, about 3–5% of all circulating cell-free DNA comes from the fetus. Cell-free fetal DNA has led to the development of several noninvasive tests using maternal blood to directly determine the fetal status, Dr. Lo explains. He notes that this discovery has allowed amniocentesis to be deferred in some cases.
One such example is the test for rhesus factor, a problem in about 15% of pregnancies. “By testing the mother’s blood for the Rh antigen of the fetus, we could potentially avoid the unnecessary use of Rh immunoglobulin (a blood product) in nearly 200,000 women in the U.S. alone,” comments Roger Lenke, M.D., director of the Indiana Center for Prenatal Diagnosis.
“Another—potentially more dramatic—use of cell-free DNA would be in the detection of fetal chromosome abnormalities. Current maternal serum tests for Down syndrome are based on indirect associations and only give the mother a risk, not an answer. The current screening tests have both high false-positive and false-negative rates.”
Several companies are developing ccff-based tests for Down syndrome. Sequenom is proceeding with a DNA-based method for the detection of trisomy 21 using massively parallel shotgun sequencing.
The technology enables detection of the additional chromosome by quantitating the volume of short sequences corresponding to chromosome 21, according to the company. Last month, Sequenom initiated a pivotal clinical study in which samples from high-risk pregnancies will be analyzed. These blinded studies are designed to support launch of a noninvasive T21 laboratory-developed test.
Future applications of shotgun sequencing of ccff DNA include early identification of cystic fibrosis, beta thalassemia, or congenital adrenal hyperplasia, all of which could potentially be treated in utero. Detection of elevated levels of circulating fetal DNA may even enable the early diagnosis of pre-eclampsia. Similar molecular analysis principles could be applied to other types of foreign DNA, such as circulating tumor DNA or DNA from organ transplants.